Metabolic and electrocardiographic effects of albuterol in pediatric asthmatic patients treated in an emergency room setting

Allergol et Immunopathol 1999;27:18-23.

Metabolic and electrocardiographic effects of albuterol in pediatric asthmatic patients treated in an emergency room setting

B. Del Río-Navarro*, A. Gazca-Aguilar*, J. A. Quibrera Matienzo**, Y. Rodríguez Galván* and J. J. L. Sienra-Monge

*Neumology and Allergy Department. **Cardiology Department. Hospital Infantil de México "Federico Gómez". México.

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SUMMARY

ß2 agonists are first election drugs for the treatment of asthma exacerbations. However, rates of complications derived from this asthma therapy like cardiovascular effects have addressed question marks on a possible paradoxical condition, leading to an increased mortality rate.

The study was open label, non controlled and aimed to assess the effect of albuterol nebulizations on serum potassium levels, arterial oxygen saturation and electrocardiographic changes in asthma exacerbation in pediatric patients. Albuterol was administered at a dose of 150 mcg/kg/course for 10 minutes in two occasions. Thirty children with mild to moderate asthmatic exacerbation, admitted to emergency room, were included in the study. Bronchodilators administration in the previous 24 hours and history of cardiac or metabolic disease were considered exclusion criteria. Drugs affecting serum potassium were not allowed. Severity of exacerbation was rated by the Wood-Downes criteria.

Average sample age was 7.4 ± 1 years, heart rate increased from 111 ± 23.23 to 130.0 ± 22.14 beats/minute, with no clinical significance; serum potassium levels decreased from 4.47 ± 0.52 to 3.73 ± 0.49 mEq/L between baseline and final visits, respectively; QTc interval was significantly enlarged from 0.397 to 0.418 milliseconds between initial and final records (p < 0.001), but had no clinical meaning. No arrhythmias were recorded. Pulse oxymetry did not show significant changes (90.6 ± 3.0% and 92.1 ± 3.2% at baseline and final visits). The most common reported adverse event was distal tremor, which was present in 80% of the cases.

Neither serum potassium decrement nor prolonged QTc after albuterol had clinical significance. Albuterol is a safe drug for the treatment of mild to moderate asthma exacerbations in pediatric patients.

Key words: Asthma. Albuterol. Cardiovascular effects.

RESUMEN

Los beta 2 agonistas son los fármacos de elección para el tratamiento de las exacerbaciones asmáticas. Sin embargo, la frecuencia de complicaciones derivadas de esta terapia del asma, tales como efectos cardiovasculares, han planteado interrogativos sobre la posible existencia de un cuadro paradójico que aumenta la mortalidad.

Este estudio abierto, no controlado, se examinó el efecto de las nebulizaciones de albuterol sobre el potasio sérico, la saturación arterial de oxígeno y las alteraciones electrocardiográficas durante las exacerbaciones asmáticas de pacientes pediátricos. Se administró albuterol a una dosis de 150 mcg/kg/ciclo durante 10 minutos y se repitió la dosis una segunda vez. Se incluyeron en el estudio 30 niños con una exacerbación asmática de intensidad entre leve y moderada que fueron asistidos en urgencias. La administración de broncodilatadores en las 24 horas anteriores y la historia de enfermedad cardíaca o metabólica fueron consideradas criterios de exclusión. No se admitió el uso de fármacos que podían modificar el potasio sérico. La gravedad de la exacerbación fue calificada utilizando los criterios de Wood-Downes.

La edad media de los pacientes de la muestra fue de 7,4 ± 1 años. Entre la consulta basal y la última, aumentó la frecuencia cardíaca de 111 ± 23,23 a 130,0 ± 11,14 latidos/minuto (sin repercusiones clínicas); disminuyó el nivel de potasio sérico de 4,47 ± 0,52 a 3,73 ± 0,49 mEq/L; y aumentó el intervalo QTc significativamente de 0,397 a 0,418 milisegundos (p < 0,001) (sin repercusiones clínicas). No se registraron arritmias. La oximetría de pulso no mostró cambios significativos (90,6 ± 3,0% y 92,1 ± 3,2% en la consulta basal y la última). El efecto adverso más frecuentemente comunicado fue temblor distal, presente en el 80% de los casos.

Ni la disminución del potasio sérico ni la prolongación del QTc que se produjeron después de la administración de albuterol tuvieron repercusiones clínicas. El albuterol es un fármaco inocuo para el tratamiento de las exacerbaciones asmáticas de intensidad entre leve y moderada en pacientes pediátricos.

Palabras clave: Asma. Albuterol. Efectos cardiovasculares.

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INTRODUCTION

Asthma is one of the most common disorders in pediatrics; it accounts for considerable number of hospitalizations every year (1). Despite advances on the knowledge of mechanisms of the disease, mortality and morbidity rates resulting from complications are still commonly reported (2). Rationale for such paradox is still under speculation, but questions marks have been addressed on the safety of some of the antiasthmatic drugs.

Durig the sixties, high doses of isoprenaline were associated to increasing mortality (3). Years later, Crane et al and Pearce and associates (4, 5) reported results in two separate case and control studies where increased mortality by asthma was related to excessive use of fenoterol. In a cohort of 12,301 individuals whose ages were between 5 and 54 years, Suissa and associates (6) investigated in Canada, the association between theophylline and beta 2 agonists to cardiovascular mortality; the found that mortality rates were higher in patients exposed to theophylline and beta 2 agonists, either by oral or nebulized routes, but nor for inhales from pressure metered dose (PMD''s) devices. One criticism to this study was the fact that most of the cardiovascular deaths occurred in patients who already had clinical or pathological evidence for potentially lethal conditions.

Because of their natural action on cardiovascular and metabolic systems, ß2 agonists have received more attention in regard with association to higher cardiovascular morbidity and mortality rates. Common adverse effects reported with these drugs are cardiac muscle isoenzimes elevation, particularlay related to excessive use of isoproterenol (7-10) and electrocardiographic disorders,such as long QT-U interval, prolonged QRS complex, changes in ST segment or even arrhythmias, like ventricular or supraventricular extrasystoles (11).

Regarding metabolism, hypokalemia is the most relevant disturbance related to beta 2 agonists, an event that may also affect cardiac activity. Furthermore, concomitant use of other antiasthmatic drugs, such as steroids o terbutaline, can lower serum potassium levels yet more.

Some authors showed that the frequency and severity of cardiovascular and metabolic disorders are directly related to dose and route of administration. The oral and parenteral administrations are more frequently associated to the adverse events (12, 13).

The information about the safety and tolerability of ß2 agonist on asthma is scare. Bentur and associates (14), evaluated the effect on arterial oxygen saturation and the relation the ship to the symptomatology in children. After two courses of albuterol nebulizations in children of 2 years and younger, they concluded that albuterol reduced arterial oxygen saturation in less then 2%, with an evident clinical benefit.

Other authors like Bierman and associates (15), evaluated the impact of these drugs on forced expiratory volume in one second (FEV₁), heart rate, blood pressure, respiratory rate and electrocardiographic changes at different inhaled doses of the ß2 agonist, bitoterol, in children 2 to 12 years; their results showed that this drug was an effective bronchodilator with minimal side effects. No significant electrocardiographic changes were recognized in this study.

Alternatively, Katz and Craig (16, 17) evaluated cardiotoxicity of albuterol administered by continuous nebulization to pediatric patients; they measured creatinine phosphokinase serum levels at baseline and after therapy, and recorded a post-treatment electrocardiogram. Changes observed were irrelevant.

Montgomery and associates (18), reported a good clinical response, without overt cardiotoxicity or hypokalemia, after the application of ß2 agonists through continuous nebulization. One drawback to this study is sample size, they only included 7 children with status asthmaticus. Papo and associates (19) also confirmed an adequate safety profile and absence of significant cardiovascular events with the use of ß2 agonists, though the primery objective of their study was to compare continuous versus intermittent nebulizations.

At present, reports assessing the use of albuterol for asthma exacerbations and its effect on metabolic, electrocardiographic and arterial oxygen saturation have been studies as isolated events. The purpose of the present study was to evaluate the correlation of albuterol nebulizations in asthma exacerbation with three different parameters in pediatric patients.

MATERIAL AND METHODS

This was an open label, non randomized study. The protocol was submitted to and approved by the Hospital''s Ethics Committee. After a detailed explanation to patients and/or tutors and having obtained their informed consent to participate in the study, children attending the emergency room at the Hospital Infantil de México "Federico Gómez", because of mild to moderate asthma exacerbations, were assessed to be included in the study. Inclusion criteria were either gender, age between 5 and 15 years, and no exposure to bronchodilators in the previous 24 hours (including ß2 agonists, methylxantines and anticholinergics).

Patients requiring the use of drugs capable to interfere with potassium metabolism were not accepted for the study, nor patients with a history of cardiac disease, electrocardiographic abnormalities at baseline, or those whose compliance to nebulized albuterol application would be unpredictable.

All patients were scored according to the Wood-Downes Diagnosis of Respiratory Failure clinical rating scale (table I) (20). The score was obtained by means of the PaO₂, or evidence of cyanosis (oxygenation), respiratory murmurs at inspiration (gas interchange), use of accessory muscles (respiratory work) and respiratory wheezing (air pathways obstruction), as well as cerebral function. Each parameter was scored in a range between 0 and 2, depending on its severity. Once patients were clinically selected (patients scoring ¾ 4), a blood sample was withdrawn for serum potassium determination, and a electrocardiogram (ECG) and arterial blood oxygen saturation test were performed.

Table I Clinical asthma evaluation score*
	0	1	2
PO2 or	70-100 in air	>= 70 in air	>= 70 in 40% O2
Cyanosis	None	In air	In 40% O2
Inspiratory breath sounds	Normal	Unequal	Decreased to absent
Accesory muscles used	None	Moderate	Maximal
Expiratory wheezing	None	Moderate	Marked
Cerebral function	Normal	Depressed or Agitated	Coma
*This score is designed for use in children with status asthmaticus. A score of 5 or more is thought to be indicative of impending respiratory failure. A score of 7 or more with an arterial carbon dioxide tension (PCO2) 65 mmHg indicates existing respiratory failure.
**Arterial oxigen tension (20).

Serum potassium levels were measured by means of a Bio-Medical Nucleus Nova (Walthman, Massachusetts, USA) device and using the electrodes technique. Normal range values for serum potassium for this study were 3.5 to 4.5 mEq/L for patients older than 3 months. ECG was obtained by using a Hewlett Packard 474 5 A Page Writer electrocardiograph model (USA), strip speed was set at 25 mm/sec. QT interval was corrected (QTc) according to the equation described by Bazett (21).

Electrocardiographic recording was performed at all leads, but measurements for QTc were made at DII and V6 only. Oxygen saturation was measured by a pulse oxymeter, model 515 A, with automatic calibration (Novametron Medical System, Inc, USA); the sensor meter was placed on the left hand middle finger.

Once a complete history and physical examination were performed, and after inclusion criteria were met, albuterol nebulizations were started (albuterol was manufactured by Glaxo Laboratories of Mexico and according to the formula by Allen & Hansbury, LTD, London E2, UK); test drug dose was set at 150 mcg/kg/course and it was diluted in 3 ml of saline solution 0.9% at room temperature. Nebulizations were dispensed with a Hudson nebulized (USA) for 10 minutes and oxygen at 4 L/min was utilizaed as propelent source.

A second nebulization course was indicated, following the procedure previously mentioned after 20 minutes. Adverse events were closely monitored, particularly tremor, nausea, vomit and tachycardia.

After 15 minutes from the two nebulization courses, a second ECG was obtained, as well as serum potassium levels and pulse oxymetry, following the procedures previously described.

Statistical analysis was performed using paired t test and a significant difference was set al < 0.05 for p values.

RESULTS

Thirty patients met inclusion criteria to enter the study, nineteen males and 11 females; average age was 7.4 ± 1.2 years. Pre treatment Wood-Downes average score was 4 and post treatment 2. Average oxygen saturation slightly increased from 90.6 ± 3.2% to 92.0 ± 3.2%, at baseline and final, respectively (table II). Average heart rate presented a non significant increment at final when compared to baseline values (table III).

Table II Average percentage of oxygen saturation (pulse oxymetry) pre and postreatment with nebulized albuterol in pediatric patients with an asthmatic crisis
	Pretreatment (%)	Post-treatment (%)
Average	90.6	92
Standard deviation	3.0	3.2
Minimum	80	90
Maximum	97	98

Table III Average heart rate before and after nebulized albuterol in pediatric patients with asthmatic crisis
	HR (beats/min)		Reference values* by age ranges HR (beats/min)
	Pretreatment	Post-treatment	4-5 years	6-8 years	9-12 years
Average	111	130	100	100	80
Standard deviation	2.3	4.0
Minimum	73	85	60	60	50
Maximum	156	173	150	140	110
*J. Salazar-Mena. Patrones electrocardiográficos en niños sanos. En: Cardiología Pediátrica. Pedro A. Sánchez Sáinz (ed). Salvat 1946:1328-9.
HR = heart rate.

None of the measured intervals but QTc, showed differences between baseline and final ECGs (tables IV-VII); enlargement recorded for final QTc in comparison to baseline measurements was statistically significant (p < 0.001), but the magnitude did not represent clinical significance (table VII). Arrhythmias were not recorded in any case.

Table IV Baseline value for AP on the electrocardiogram before and after nebulized albuterol in pediatric patients with asthma crisis
	AP (°)
	Pretreatment (%)	Post-treatment (%)
Nº. of cases	30	30
Average	60.50	60.50
Standard deviation	6.20	6.20
Standard error	1.13	1.13
Minimum	45.00	45.00
Maximum	90.00	90.00
AP = atrial vector.

Table V Baseline values of AQRS interval on the electrocardiogram before and after nebulizad albuterol in pediatric patients with asthmatic crisis
	AQRS (°)		Reference values* by age ranges AQRS (°)
	Pretreatment	Post-treatment	4-5 years	6-8 years	9-12 years
N.º de cases	30	30
Average	64,83	65.66	60	60	60
Standard deviation	44.18	44.09
Standard error	8.068	8.051
Minimum	-150.00	-150.00	0	-20	20
Maximum	90.00	100.00	100	100	100
*J. Salazar-Mena. Patrones electrocardiográficos en niños sanos. En: Cardiología Pediátrica. Pedro A. Sánchez Sáinz (ed). Salvat 1946: 1328-9.
AQRS = QRS complex vector.

Table VI Baseline values of P-R interval on the electrocardiogram before and after nebulizaed albuterol in pediatric patients with asthmatic crisis
	PR ('''')		Reference values* by age ranges PR ('''')
	Pretreatment	Post-treatment	4-5 years	6-8 years	9-12 years
N.º de cases	30	30
Average	0.130	0.126	0.12	0.13	0.14
Standard deviation	0.010	0.012
Standard error	0.002	0.002
Minimum	0.110	0.110	0.1	0.11	0.11
Maximum	0.150	0.150	0.18	0.20	0.20
*J. Salazar-Mena. Patrones electrocardiográficos en niños sanos. En: Cardiología Pediátrica. Pedro A. Sánchez Sáinz (ed). Salvat 1946: 1328-9.

Table VII Values of QTc interval on the electrocardiogram before and after nebulized albuterol in pediatric patients with asthmatic crisis
	QT ('''')		Reference values* by heart rate QT ('''')
	Pretreatment	Post-treatment		70	80	90	100	120	150	180
N.º de cases	30	30
Average	0.397	0.418		0.3	0.3	0.3	0.3	0.2	0.2	0.2
				7	5	3	0	8	5	3
Standard deviation	0.030	0.039
Standard error	0.005	0.007
Minimum	0.340	0.320		0.3	0.2	0.2	0.2	0.2	0.2	0.1
				2	9	7	6	4	1	9
Maximum	0.450	0.520		0.4	0.4	0.3	0.3	0.3	0.2	0.2
				3	0	7	5	2	8	7
*J. Salazar-Mena. Patrones electrocardiográficos en niños sanos. En: Cardiología Pediátrica. Pedro A. Sánchez Sáinz (ed). Salvat 1946: 1328-9.

Pre treatment serum potassium levels were in the range of 3.2-5.6 mEq/L, but after albuterol exposure, ranges went down to 2.0-4.5 mEq/L (table VIII). One patients showed remarkable decrement in serum potassium value, but no haemodynamic or electrocardiographic consequences were identified.

Table VIII Average serum potassium levels before and after nebulized albuterol in pediatric patients with asthmatic crisis
	serum K + (mEq/l)
	Pretreatment	Post-treatment
Average	4.4	3.7
Standard deviation	0.52	0.49
Minimum	3.2	2.0
Maximum	5.6	4.5

Despite the trend to prolonged QTc, no interrelationship with serum potassium levels was demonstrated.

Adverse events secondary to albuterol were limited to the cardiovascular and neuromuscular systems. Distal fine tremor was reported in 80% of the subjects.

DISCUSSION

During late 1970 and early 1980, substantial increments in mortality rate associated to children with asthma were reported in Australia, England, Canada, Holland, Switzerland, France, Germany, Israel, United States and Denmark (2). By late 1980, some of these countries recorded steady states and even declines in mortality rates. Even with this significant trend change, present mortality rate related to asthma remains > 50% higher than figures reported in early seventies (22-24). Risk factors contributing to such high rates have not been elucidate yet, though some investigators have incriminated pollution, occupational hazards, severity of exacerbation crises, time elapsed to receive medical attention or type of antiasthmatic therapy, among others.

Use of ß2 agonists in children in extremely common, either for acute crisis management or for prophylaxis of exercise induced bronchospasm. Other frequent indications are long term treatment or maintenance therapy.

In adults, high doses of ß2 agonists are related to more common adverse events, including fast decrement of serum potassium levels (25). Beside ß2 agonists, other factors also contributing to hypokalemia are: concomitant use of steroids or teophylline, hypoxemia. When these drugs are given orally, the risk of developing tachycardia, QT enlargement, angina or ventricular ectopia es increased (6). Each drug in this therapeutic class has a slightly different cardiotoxicity profile, as Newhouse and Bremner reported (11, 26).

Safety profile of ß2 agonists in pediatric population has not been thoroughly explored, partly because clinical trials in children are difficult as a result of poor compliance to spirometric maneuvers, blood sample withdrawals or dosing schedule.

In our study, standard doses of intermittently nebulized albuterol seemingly produced hypokalemia; however, such changes were not significant, neither clinical nor statistical and no haemodinamic change was recorded at any moment. Our findings on potassium reduction are in accordance to those reported by other authors (18, 19), they separately indicated that changes without clinical relevance were recorded in serum potassium.

Similar to the observations reported by Craig (17), none of our patients developed cardiac arrhythmias, myocardial ischemia or chest pain. However, we identified that QT was significantly prolonged in our patients after the exposure to nebulized albuterol, but with no clinical relevance. This electrocardiographic disorder on QT interval, resembles that reported by other author (16), after the use of beta 2 agonists.

Changes in pulse oxymetry went towards a better oxygen saturation, but the magnitude of the effect was minimal and with no clinical significance. Such findings are in parallel with those reported by Bentur and associates (14).

In contrast to the previous report by Bierman, tremor was the most frequent adverse event in this study; it was suffered by 80% the patients and was associated with tachycardia.

Undoubtedly, high morbidity and mortality rates secondary to asthma, enough motivate to continue searching for the factors generating these conditions. Lack of identification or no immediate actions taken during a severe exacerbation may importantly contribute to disappointing results (27).

Patients included in our study carried mild to moderate exacerbations and had no cardiovascular or metabolic compromise. Beside, all drugs potentially able to modify serum potassium levels were excluded from the study. This condition is rare in common medical practice, where concomitant use of xanthines or steroids are the rule; interactions between these drugs and beta 2 agonists might affect potassium levels more evidently, to the point of becoming clinically significant.

Our study supports the fact that in pediatric patients, with mild to moderate asthmatic exacerbation, not requiring concomitantly other antiasthmatic drugs, use of albuterol has an adequate cardiovascular and metabolic safety profile.

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Correspondence:

Juan José L. Sienra-Monge

Hospital Infantil de México "Federico Gómez"

Dr. Márquez 162, Col. Doctores

Ciudad de México, 06720 México